Glucocorticoids antagonize estrogens by glucocorticoid receptor-mediated activation of estrogen sulfotransferase.
Glucocorticoids antagonize estrogens by glucocorticoid receptor-mediated activation of estrogen sulfotransferase.
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DOI：
10.1158/0008-5472.can-08-1545
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发表时间：
2008-09-15
期刊：
影响因子：
11.2
通讯作者：
Xie W
中科院分区：
文献类型：
--
作者：
Gong H;Jarzynka MJ;Cole TJ;Lee JH;Wada T;Zhang B;Gao J;Song WC;DeFranco DB;Cheng SY;Xie W
糖皮质激素和雌激素是两类类固醇激素，具有基本但不同的生理功能。雌激素也是乳腺癌的一个危险因素。有人认为糖皮质激素可以减弱雌激素反应，但糖皮质激素抑制雌激素活性的机制尚不清楚。在这项研究中，我们发现地塞米松（DEX）激活糖皮质激素受体（GR）诱导雌激素硫转移酶（SULT1E1或EST）的表达和活性，这是一种对雌激素代谢失活很重要的酶，因为磺化的雌激素不能激活雌激素受体。在体外和异种移植模型中，DEX治疗降低了循环雌激素，损害了子宫雌激素反应，抑制了雌激素依赖性乳腺癌的生长。我们进一步发现小鼠和人类SULT1E1基因是GR的转录靶点，小鼠中SULT1E1 /Est的缺失消除了DEX对雌激素反应的影响。这些发现揭示了一种新的核受体介导和基于代谢的雌激素剥夺机制，这可能对乳腺癌的治疗发展有影响。由于糖皮质激素和雌激素是广泛使用的处方药，我们的研究结果也敦促患者谨慎避免糖皮质激素-雌激素相互作用。
Glucocorticoids and estrogens are two classes of steroid hormones that have essential but distinct physiologic functions. Estrogens also represent a risk factor for breast cancer. It has been suggested that glucocorticoids can attenuate estrogen responses, but the mechanism by which glucocorticoids inhibit estrogenic activity is unknown. In this study, we show that activation of glucocorticoid receptor (GR) by dexamethasone (DEX) induced the expression and activity of estrogen sulfotransferase (SULT1E1 or EST), an enzyme important for the metabolic deactivation of estrogens, because sulfonated estrogens fail to activate the estrogen receptor. Treatment with DEX lowered circulating estrogens, compromised uterine estrogen responses, and inhibited estrogen-dependent breast cancer growth in vitro and in a xenograft model. We further showed that the mouse and human SULT1E1 genes are transcriptional targets of GR and deletion of Sult1e1/Est in mice abolished the DEX effect on estrogen responses. These findings have revealed a novel nuclear receptor–mediated and metabolism-based mechanism of estrogen deprivation, which may have implications in therapeutic development for breast cancers. Because glucocorticoids and estrogens are widely prescribed drugs, our results also urge caution in avoiding glucocorticoid-estrogen interactions in patients.